Severe, rapidly progressive human immunodeficiency virus type 1 disease in newborns with coinfections.

AIM: To describe a severe form of rapidly progressive HIV-1 infection manifesting in the neonatal period. METHOD: Prospective cohort study, King Edward VIII Hospital, Durban, South Africa. HIV-1-exposed neonates with hepatosplenomegaly, lymphadenopathy or persistent pneumonia within the first 28 days of life were investigated for perinatal infections. Confirmation of neonatal HIV-1 infection, HIV-1 subtype and clinical outcomes were studied. RESULTS: Twenty-three (72%) of 32 symptomatic HIV-1-exposed neonates recruited at a mean of 15.2 days were HIV-1-infected. HIV-1 infection was detected in 5 patients who were tested within 48 h of birth, confirming congenital infection. Congenital infection was not excluded in any case. Median neonatal viral load at recruitment was 471,932 copies/ml and median CD4 was 777 cells/mm3. The predominant clinical presentation was growth retardation and prematurity. Perinatal infections detected included: tuberculosis (8), syphilis (6) and cytomegalovirus (10). All of the neonates with perinatal tuberculosis were HIV-1-coinfected. Maternal and neonatal viral load and CD4 at recruitment were not statistically different between the groups with tuberculosis vs. other coinfections. Gag gene sequence analysis confirmed closely aligned HIV-1 subtype C in mothers and neonates. Nineteen (83%) died by 9 months, with a mean age at death of 3.5 months. CONCLUSIONS: A distinct group of HIV-1-infected babies may clinically manifest in the neonatal period with perinatal coinfections, subsequent rapidly progressive HIV-1 and early death.

Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum.

Multilocus genotyping of microbial pathogens has revealed a range of population structures, with some bacteria showing extensive recombination and others showing almost complete clonality. The population structure of the protozoan parasite Plasmodium falciparum has been harder to evaluate, since most studies have used a limited number of antigen-encoding loci that are known to be under strong selection. We describe length variation at 12 microsatellite loci in 465 infections collected from 9 locations worldwide. These data reveal dramatic differences in parasite population structure in different locations. Strong linkage disequilibrium (LD) was observed in six of nine populations. Significant LD occurred in all locations with prevalence <1% and in only two of five of the populations from regions with higher transmission intensities. Where present, LD results largely from the presence of identical multilocus genotypes within populations, suggesting high levels of self-fertilization in populations with low levels of transmission. We also observed dramatic variation in diversity and geographical differentiation in different regions. Mean heterozygosities in South American countries (0.3-0.4) were less than half those observed in African locations (0. 76-0.8), with intermediate heterozygosities in the Southeast Asia/Pacific samples (0.51-0.65). Furthermore, variation was distributed among locations in South America (F:(ST) = 0.364) and within locations in Africa (F:(ST) = 0.007). The intraspecific patterns of diversity and genetic differentiation observed in P. falciparum are strikingly similar to those seen in interspecific comparisons of plants and animals with differing levels of outcrossing, suggesting that similar processes may be involved. The differences observed may also reflect the recent colonization of non-African populations from an African source, and the relative influences of epidemiology and population history are difficult to disentangle. These data reveal a range of population structures within a single pathogen species and suggest intimate links between patterns of epidemiology and genetic structure in this organism.

Sequence diversity of TT virus in geographically dispersed human populations.

TT virus (TTV) is a newly discovered DNA virus originally classified as a member of the Parvoviridae. TTV is transmitted by blood transfusion where it has been reported to be associated with mild post-transfusion hepatitis. TTV can cause persistent infection, and is widely distributed geographically; we recently reported extremely high prevalences of viraemia in individuals living in tropical countries (e.g. 74% in Papua New Guinea, 83% in Gambia; Prescott & Simmonds, New England Journal of Medicine 339, 776, 1998). In the current study we have compared nucleotide sequences from the N22 region of TTV (222 bases) detected in eight widely dispersed human populations. Some variants of TTV, previously classified as genotypes 1a, 1b and 2, were widely distributed throughout the world, while others, such as a novel subtype of type 1 in Papua New Guinea, were confined to a single geographical area. Five of the 122 sequences obtained in this study (from Gambia, Nigeria, Papua New Guinea, Brazil and Ecuador) could not be classified as types 1, 2 or 3, with the variant from Brazil displaying only 46-50% nucleotide (32-35% amino acid) sequence similarity to other variants. This study provides an indication of the extreme sequence diversity of TTV, a characteristic which is untypical of parvoviruses.

Genetic heterogeneity of HIV type 1 subtypes in Kimpese, rural Democratic Republic of Congo.

A relatively low and stable seroprevalence of HIV-1 was previously reported among pregnant women attending for antenatal care between 1988 and 1993 in Kimpese, a rural town in the Democratic Republic of Congo (DRC, formerly Zaire). To characterize the HIV-1 subtypes circulating in this area, we have examined a 330-bp fragment of the p17 region of the gag gene of HIV-1 strains obtained from 70 patients (55 mothers, 15 children), of whom 61 were epidemiologically unlinked. Phylogenetic analyses revealed the existence of at least seven HIV-1 subtypes within the Kimpese region. Among the 61 epidemiologically unlinked patients, subtype A was predominant and found in 29 (47.5%) individuals. Other subtypes cocirculating in this rural part of DRC include subtypes C (1.6%), D (9.8%), F (3.2%), G (6.5%), H (21.3%), and J (4.9%). Sequences from four patients did not cluster with any of the currently documented HIV-1 subtypes, in analyses of fragments of both the gag (247 to 330 bp, 197 bp, and 310 bp) and env (340 bp) genes. Overall, comparisons of the gag(p17) gene regions revealed high pairwise divergences (mean, 19.9%; range, 1 to 46%). This level of gag(p17) gene variation in the DRC is considerably greater than previously appreciated. These results are relevant for the molecular epidemiology of HIV-1 in Africa and for the design of a future vaccine against HIV-1 in this region.

Early acquisition of TT virus (TTV) in an area endemic for TTV infection.

TT virus (TTV) is widely distributed, with high frequencies of viremia in South America, Central Africa, and Papua New Guinea. The incidence and timing of infection in children born in a rural area of the Democratic Republic of Congo was investigated. TTV viremia was detected in 61 (58%) of 105 women attending an antenatal clinic and in 36 (54%) of 68 infants. Most infants acquired the infection at >/=3 months postpartum. Surprisingly, TTV infection was detected in a large proportion of children with TTV-negative mothers (13 [43%] of 30). Nucleotide sequences of TTV-infected children were frequently epidemiologically unlinked to variants detected in the mother. These three aspects contrast with the maternal transmission of hepatitis G virus/GB virus C in this cohort and suggest an environmental source of TTV infection comparable to hepatitis A virus and other enterically transmitted infections.

Discrimination of hepatitis G virus/GBV-C geographical variants by analysis of the 5' non-coding region.

We have investigated the ability of different subgenomic fragments to reproduce the phylogenetic relationships observed between six complete genome sequences of GBV-C/hepatitis G virus (HGV). While similar relationships were observed following analysis of part of the 5' non-coding region (5'NCR), for the coding region they were not accurately reproduced for some large fragments or for the majority of fragments of 300 or 600 nucleotides. Analysis of 5'NCR sequences from a large number of isolates, including newly obtained sequences from Pakistan, Zaïre and Scotland, produced separate groupings of Asian, African and European/North American variants. These groupings are associated with specific polymorphisms in the 5'NCR, many of which were covariant and consistent with a proposed secondary structure for this region. The relatively low level of amino acid sequence variation observed between these geographically and phylogenetically defined groups of variants suggests that they are unlikely to display significant biological differences.

How valuable are IgA and IgM anti-HIV tests for the diagnosis of mother-child transmission of HIV in an African setting?

BACKGROUND: Babies born to HIV-infected mothers retain anti-HIV of maternal origin until 15-18 months of age. Because of this, HIV proviral DNA and p24 antigen measurements have become the methods of choice for timely diagnosis of HIV infection in infancy. They are, however, too expensive for widespread use in the developing world. OBJECTIVE: To evaluate a simple, inexpensive serological method for diagnosing mother-child transmission of HIV, in an African population, which takes account of the effects of placental transfer of maternal antibody and continued exposure to HIV through breast-feeding. STUDY DESIGN: Plasma specimens for a prospective study of mother-to-infant transmission of HIV in rural Zaire were collected at birth, 3, 6, 9, 12, 18 and 24 months from 21 infected infants (PP group), 21 uninfected infants (PN group) born to seropositive mothers and 21 control infants (NN group) born to uninfected mothers. The specimens were retrospectively tested for IgG, IgM and IgA anti-HIV by immunoglobulin class-specific capture EIAs, and by a commercial anti-HIV EIA. RESULTS: In neonatal specimens, IgA and IgM anti-HIV were present, respectively, in 13 of 14 (97%) and 8 of 14 (57%) of the PP group and in 6 of 11 (55%) and 2 of 11 (18%) of the PN group. Later, at 3 months and older, IgA and IgM anti-HIV were only detected in the PP group. They peaked at 18 months (93%) and 24 months (67%) respectively. Of the 21 PP group children, 8 (38%) were transiently IgG anti-HIV-negative in the first year, indicating that infection had probably taken place after birth; four of the 8 had no detectable IgA anti-HIV during the first year. None of the specimens collected from the NN group babies were reactive for IgA, IgM or IgG anti-HIV. CONCLUSIONS: IgA and IgM anti-HIV may be passively transferred across the placenta. Where breast-feeding is prevalent, about half of the transmissions may occur after birth, thus delaying the diagnosis of mother-child transmission. Nevertheless, this simple, cheap IgA anti-HIV, EIA identified 65% of transmissions by 9 months of age, and 93% at 18 months of age. It is a more useful marker than IgM anti-HIV, and gave a much more rapid answer than did tests for IgG anti-HIV seroreversion.

A preliminary evaluation of the cognitive and motor effects of pediatric HIV infection in Zairian children.

Fourteen asymptomatic HIV-infected Zairian children under 2 years of age displayed social and motor developmental deficits on the Denver Developmental Screening Test when compared with 20 HIV-negative cohorts born to HIV-infected mothers and 16 control children. In a second study, 11 infected children over 2 years of age had sequential motor and visual-spatial memory deficits on the Kaufman Assessment Battery for Children and motor development deficits on the Early Childhood Screening Profiles. HIV infection affects central nervous system structures mediating motor and spatial memory development, even in seemingly asymptomatic children. Furthermore, maternal HIV infection compromises the labor-intensive provision of care in the African milieu and undermines global cognitive development in even uninfected children.

PIP: Language and motor skill deficits have been noted for HIV-infected children when tested with Stanford-Binet. With the McCarthy Scales of Children's Abilities, quantitative, verbal, and memory ability deficits have also been documented with infected children and are particularly significant for those children with accompanying neurological impairment from the virus. Deficits of visual-spatial integrative ability and memory have also been identified with the Kaufman Assessment Battery for Children. This paper reports results from a direct comparison of differences in cognitive and motor skills development between HIV-1-seropositive and HIV-1-seronegative children born to infected African mothers. Both subgroups were subsequently compared to a third group of HIV-negative children born to noninfected mothers in order to better assess some of the second-order effects of the epidemic upon the development of children who are not themselves infected, but who bear the consequences of the disease in the form of illness of the primary caregiver, and the hardship which that imposes upon the entire family. Such factors are most likely especially severe for nonaffluent families in developing countries. 14 asymptomatic HIV-infected Zairian children under 2 years old displayed social and motor developmental deficits on the Denver Developmental Screening Test when compared with 20 HIV-negative cohorts born to HIV-infected mothers and 16 control children. In the second study, 11 infected children over 2 years old had sequential motor and visual-spatial memory deficits on the Kaufman Assessment Battery for Children and motor development deficits on the Early Childhood Screening Profiles. The authors conclude that HIV infection affects central nervous system structures mediating motor and spatial memory development, even in seemingly asymptomatic children. Moreover, maternal HIV infection compromises the labor-intensive provision of care in the African milieu and undermines global cognitive development in even uninfected children.

L'interet d'un regime therapeutique de charge par la quinine au cours du neuropaludisme chez l'enfant : resultats preliminaires

Les auteurs presentent les resultats d'une enquete retrospective courant du 1er janvier 1990 au 31 decembre 1993 et portant l'evaluation de l'efficacite clinique d'un regime therapeutique de charge par la quinine en perfusion intraveineuse au cours du neuropaludisme chez l'enfant. Le regime therapeutique utilise consiste en une perfusion intraveineuse de 20 mg de quinine par kilo de poids corporel dans le serum glucose a 5 pour cent (10 mg de quinine pour 10 ml de serum glucose a 5 pour cent). Le temps de perfusion est de 4 heures; la perfusion est suivie par des doses orales de quinine (30mg par Kilo de poids corporel par 24 heures en 3 prises) pendant 7 jours. Sous ce traitement; 76 pour cent de malades ont eu une recuperation clinique totale; le taux de letalite est de 18 pour cent et le taux de sequelles 6 pour cent. 98 pour cent d'enfants ayant consulte endeans les 24 heures du debut des manifestations neurologiques ont eu une recuperation clinique totale. La conscience est recuperee chez 66 pour cent des cas endeans les 24 heures de l'instauration du traitement. 83 pour cent de l'ensemble de sequelles et 100 pour cent de deces sont rencontres dans le groupe d'enfants ayant consulte au dela de 48 heures du debut des manifestations neurologiques. Ces resultats temoignent entre autres de l'efficacite du schema therapeutique utilise

Severe anaemia in pregnancy: a problem of primigravidae in rural Zaire.

Haemoglobin levels were measured in 2950 pregnant women attending antenatal clinics in Kimpese, Bas Zaire. 72% were suffering from moderate anaemia (haemoglobin (Hb) 7-11 g/dl) and 3.7% from severe anaemia (Hb less than 7 g/dl) at their first visit, before receiving any haematinics or anti-malarial prophylaxis. Haemoglobin levels rose with both increasing parity (P less than 0.001) and age. Multiple regression analysis revealed that parity was significant but age was not. The fall in haemoglobin early in the second trimester was greatest in primigravidae and diminished with successive pregnancies until the fourth. One in 6 primigravidae approached labour with a haemoglobin level less than 7.7 g/dl. Thick blood smears were examined from 379 women who presented in the first and second trimester. 70% of primigravidae had malaria parasitaemia, compared with 13% of multigravidae (P less than 0.001). Early malaria prophylaxis in the first 2 pregnancies is an important primary health care objective if the contribution of malaria to the significant fall in haemoglobin in the second trimester is to be averted.